title: Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma.
abstract: OBJECTIVE
  To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma.
  
  
  METHODS
  In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m(2) immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m(2) on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed.
  
  
  RESULTS
  Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m(2) and doxorubicin 60 mg/m(2). Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration.
  
  
  CONCLUSIONS
  The combination of doxorubicin 60 mg/m(2) followed by trabectedin 1.1 mg/m(2) every 21 days is safe and active in patients with soft-tissue sarcoma.
authors.affiliation: CONTICANET and UJOMM Hôpital Edouard Herrot, Centre Léon Bérard, Lyon, France. BLAY@lyon.fnclcc.fr
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Margaret
authors.initials: M
authors.lastname: von Mehren
authors.forename: Brian L
authors.initials: BL
authors.lastname: Samuels
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fanucchi
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ray-Coquard
authors.forename: Brigid
authors.initials: B
authors.lastname: Buckley
authors.forename: Leen
authors.initials: L
authors.lastname: Gilles
authors.forename: Claudia
authors.initials: C
authors.lastname: Lebedinsky
authors.forename: Yusri A
authors.initials: YA
authors.lastname: Elsayed
authors.forename: Axel
authors.initials: A
authors.lastname: Le Cesne
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004149:Dioxoles / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007890:Leiomyosarcoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D008080:Liposarcoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D012509:Sarcoma / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage; D000077606:Trabectedin; D055815:Young Adult
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; D000077606:Trabectedin